원저 J Korean Neurol Assoc / Volume 24 / August, 2006 한양대학교의과대학신경과학교실 The Relationship of Matrix Metalloproteinase-9 and Microbleeds on T 2 *-Weighted Gradient-Echo MRI in Acute Lacunar Infarction Chang-Yun Park, M.D., Dae-Lim Koo, M.D., Hyun-Young Kim, M.D., Seong-Ho Koh, M.D., Kyu-Yong Lee, M.D., Young Joo Lee, M.D., Juhan Kim, M.D., Seung Hyun Kim, M.D. Department of Neurology, College of Medicine, Hanyang University, Seoul, Korea Background: Hypointense cerebral lesions on T2*-weighted gradient-echo MRI (GRE) have been known to be related with microbleeds or advanced microangiopathy with potential for further bleeding. It has also been suggested that matrix metalloproteinases (MMPs) may play a role in blood brain barrier disruption, edema formation and hemorrhagic transformation. In this study, we investigated the relationship between microbleeds detected by GRE, MMPs and neurological worsening in acute lacunar infarctions. Methods: Eighty-eight patients with acute lacunar infarctions, defined by TOAST classification, were included. GRE (1.5T, TR 500 ms TE 15 ms) was performed within 48 hours after stroke symptom onset. MMPs were measured by standard quantitative sandwich enzyme-linked immunosorbent assays (ELISA). Clinical characteristics, neurologic scale and MMP-9 levels were compared between groups with or without hypointense lesions in GRE (microbleeds). Neurological worsening was defined as deterioration from baseline in the score on the NIHSS by one or more points 14 days after the onset of a lacunar infarction. Results: Eleven of 88 patients (12.5%) undergoing GRE demonstrated evidence of microbleeds in the ischemic region. In the groups with microbleeds, the ESR level (p=0.048) and MMP-9 activity (p=0.001) were significantly increased, and neurological worsening was more prominent (p=0.018). Conclusions: This study suggests that microbleeds detected by GRE are related with elevated MMP-9 and neurological worsening. Therefore, the finding of microbleeds in GRE, increased MMP-9 activity and elevated ESR level might be useful factors for predicting the progression of acute lacunar infarctions. J Korean Neurol Assoc 24(4):311-317, 2006 Key Words: Microbleeds, Gradient echo MRI, MMP-9, Lacunar stroke 서 론 미세출혈 (microbleeds) 은 2~5 mm 의크기를보이는뇌실질내의출혈로서혈관외유출 (extravasation) 을통해발생하며 Received November 26, 2005 Accepted February 14, 2006 *Seung Hyun Kim, M.D. Department of Neurology, Hanyang University Hospital 17 Haengdang-dong, Seongdong-gu, Seoul, 133-792, Korea Tel: +82-2-2290-8371 Fax: +82-2-2296-8370 E-mail: kimsh1@hanyang.ac.kr 임상적으로무증상인경우가대부분이다. 1 이런미세출혈은출혈성뇌졸중의 71%, 허혈성뇌졸중의 20~68%, 정상성인의 3~7% 에서나타난다고알려져있으며원인기전으로는죽상경화및고혈압성혈관병증과연관된다고한다. 3 미세출혈은경사에코자기공명영상 (T 2*-weighted gradientecho MRI; 이하 GRE) 에서뚜렷한경계를보이는원형의저음영병소로보이는데, GRE 에서저음영을보이는것은혈액파괴산물 (blood-breakdown products) 들의상자성효과 (paramagnetic effect), 혹은국소적인혈철소 (hemosiderin) 침착과연관이있 J Korean Neurol Assoc Volume 24 No. 4, 2006 311
을것이라고추정된다. 3,4 또한혈철소의존재는 matrix metalloproteinase (MMP) 의활성을유도하여기저막파괴, 염증반응에도관여한다고알려져있다. 2,3,5 저자들은최근열공성뇌경색의초기신경학적악화와 MMP-9 이연관될수있음을보고하였으나 6 자세한기전에대해서는밝히지못하였다. 이에본연구는 MMP-9 의활성과미세출혈의연관성을조사하여미세출혈에관여하는인자및급성기열공성뇌경색환자의임상경과에영향을주는인자에대해분석하였다. 대상과방법 1. 대상 2003 년 6월부터 2005 년 7월까지한양대학병원신경과에입원한뇌경색환자중 Trial of Org 10172 in Acute Stroke Treatment (TOAST) 분류상열공성뇌경색으로분류되어, 증상발생 48시간이내에자기공명영상촬영을시행한환자를대상으로하였다. 감염, 종양등의상태나 CT 또는자기공명 T1 강조영상에서뚜렷한출혈을보인경우는배제하였다. 2. 방법 (1) 뇌자기공명촬영 T1, T2 강조영상, 확산강조영상및경사에코자기공명영상 (T 2*-weighted gradient-echo MRI; GRE) 을포함한뇌자기공명촬영을시행하였다. 자기공명영상은 1.5T 초전도체자기공명영상기기 (GE Signa Horizon, U.S.A) 와 bird cag 형두부코일을이용하였다. 확산강조영상은 echo planar imaging 기법을이용하여확산경사자기를 x, y, z 세방향으로가한후등방성영상을얻었다. 확산강조영상을얻기위한영상변수로는 TR/TE=10,000 msec/96 msec, matrix=128 128, b값 =1,000 sec/mm 2, 절편두께 5 mm 로하였다. 경사에코자기공명영상은 TR/TE=500/15, matrix 128 128 를이용하였고, 절편의두께는 5 mm로하였다. 이번연구는자기공명 T1 강조영상에서는신호변화가보이지않으면서 T2 강조영상및확산강조영상에서급성기허혈성 Figure 1. Diffusion weighted (upper lane) & T 2*-weighted gradient-echo MRI (GRE) (lower lane). Arrow shows microbleeds in ischemic core and arrow head shows microbleeds in other lesion. Group 1 was defined as when hypointense lesions were found in acute ischemic lesion. And, when hypointense lesion are found in both acute ischemic lesion(s) and other silent region, they were classified as group 2. Group 3 was defined when microbleeds are found in only silent regions. Finally, group 4 was defined when microbleeds were not detected by GRE. 312 J Korean Neurol Assoc Volume 24 No. 4, 2006
뇌경색으로진단된경우를대상으로하였고, GRE 상저음영을보이는것을미세출혈이라고정의하였다. 대상은자기공명영상소견상미세출혈및허혈성병변의유무에따라 4군으로분류하였다. 확산강조영상에서급성허혈성병변이있으며, 동일부위에 GRE 상미세출혈이있는경우를제 1군, 급성병변뿐만아니라정상부위혹은타경색부위에서도 GRE 상미세출혈이있는경우를제2군, 급성기병변에서는 GRE 상미세출혈이발견되지않고정상혹은타경색부위에서만 GRE 상미세출혈이있는경우를제3 군, 확산강조영상에서급성기허혈성병변이있음에도 GRE 상미세출혈이전혀관찰되지않는경우는제4 군으로정의하였다 (Fig. 1). 또한, 열공성급성뇌경색부위외에타부위에서 GRE 상미세출혈소견이어느정도관찰되는지알아보았다. 확산강조영상에서확인된급성기허혈성병변에미세출혈을보인제1군및 2군은미세출혈의해부학적위치에따른분포를조사하였다. 또한, 급성허혈성병변이외미세출혈이있었던경우 (2군, 3군 ) 미세출혈의개수를세어서분포가어떻게되는지알아보았다. (2) 임상척도및검사실척도에대한평가각군간의연령과성비를살펴보았다. 그리고, 뇌졸중에관련된위험인자는고혈압, 당뇨, 고지혈증, 심장질환과흡연의기왕력여부로정하였다. 고혈압은환자가기존에항고혈압약제를복용하거나, 수축기혈압이 160 mmhg 이상또는이완기혈압이 95 mmhg 이상이 2번이상있는경우로, 당뇨는공복시혈당이 140 mg/dl 이상이거나당뇨치료를받고있는경우로하였다. 고지혈증은허혈성심장질환의치료기준인총콜레스테롤이 200 mg/dl 이상인경우나저비중지단백콜레스테롤이 130 mg/dl 이상인경우와고지혈증으로치료중인경우로하였다. 심장질환은고혈압성심장변화를제외한부정맥, 판막질환, 관상동맥질환이있는경우로한정하였고, 흡연은기왕력이있는경우와없는경우로나누었다. 임상척도로는체온, 혈압및 National Institute of Health Stroke Scale (NIHSS) 를포함한신경학적소견을포함하였으며, 검사실척도로는 CBC 검사를통한 Hematocrits, leukocyte, 그리고 glucose, low density lipiprotein (LDL), high density lipoprotein (HDL), triglyceride (TG) 를측정하였으며, 그외에 erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, activated partial thromboplastin time, prothrombin time, Anti-thrombin III (AT III), D- dimer, Neuron-specific enolase (NSE) 를이용하여각군간의차이를비교하였다. (3) 활성 MMP-9 의비교내원직후채취한혈액은 1500 rpm 으로원심분리를하여혈장 (plasma) 상태로 -70 에서냉장보관하였고, 추후표준정량적 Enzyme-linked immunosorbent assay (ELISA, R&D system, MN, USA: active MMP-9 fluorescent immunoassay) 를이용하여각그룹별로활성 MMP-9 을측정하였다. 활성 MMP-9 측정을위해 3개의 well 에서얻어진값들의평균을통해구했으며, 2회반복을통해재현성을확인하였다. (4) 예후평가모든대상은내원당시와증상발생 14일후에동일한검사자에의해신경학적손상을평가하였다. 신경학적손상은 NIHSS 로평가하였다. 신경학적악화의정의는내원당시 NIHSS 점수보다내원 14일후재시행한점수가 1점이상증가한경우로하였다. 그리고 GRE 상미세출혈을보인경우 (1군, 2군, 3군 ) 와미세출혈이없었던경우 (4군 ) 신경학적악화를어느정도 (%) 보이는지알아보고, 허혈성병변에미세출혈이존재하는지의여부에따른예후의차이를살펴보았다. (5) 통계분석모든통계처리는 SPSS 를이용하여 chi-square 와 One-way analysis of variance (ANOVA), 그리고 Kruskal-Wallis test 로하였으며 p-value 가 0.05 미만일때통계적으로유의성이있는것으로평가하였다. 결과 총대상환자 88명중, 자기공명영상에서급성허혈성병변에만미세출혈을보인제1군은 5명이었으며, 허혈성병변뿐만아니라타부위에도미세출혈이발생한제2 군은 6명이었고, 급성허혈성병변에는미세출혈이없고타부위에만미세출혈이있었던 3군은 25명, GRE 상미세출혈이보이지않았던 4군은 52명의분포를보였다. 허혈성병변에미세출혈을보인경우 (1 군, 2군 ) 은 11명 (12.5%) 이었고, 병소에관계없이 GRE 상미세출혈이관찰되는경우 (1군, 2군, 3군 ) 는 36명 (36.7%) 이었다. 제2군에서, 허혈성병변이외의타부위에서미세출혈의개수가 2개인경우가 1명, 3개는 3명, 그리고 5개와 7개를보인경우는각 1명씩의분포를보였다. 3군에서는미세출혈개수에따른분포는미세출혈 1개 (4명), 2개 (5명), 3개 (4명), 4개 (5명), 5 개 (3명), 6개 (1명), 7개 (1명), 12개 (1명), 14개 (1명) 의분포를보였다. J Korean Neurol Assoc Volume 24 No. 4, 2006 313
Table 1. Demographic data and risk factors in each groups Characteristics Group 1 (n=5) Group 2 (n=6) Group 3 (n=25) Group 4 (n=52) P-value Age, mean±sd Sex difference (M : F) 69.4±12.5 3:2 64.3±6.9 5:1 63.6±12.1 12 : 13 64.5±12.3 13 : 39 0.802 a Stroke Risk Factor, count (% within group) Hypertension 3 (60.0%) DM 1 (20.0%) Heart disease 0 (0%) Hyperlipidemia 1 (20.0%) Smoking 2 (40.0%) 5 (83.3%) 2 (33.3%) 1 (16.7%) 2 (33.3%) 0 (0%) 20 (80.0%) 8 (32.0%) 3 (50%) 7 (28%) 5 (20.0%) 29 (55.8%) 12 (23.1%) 2 (33.8%) 6 (11.5%) 11 (21.2%) 0.148 0.812 0.382 0.251 0.434 a by Kruskal Wallis test. 허혈성병변에서보이는미세출혈의분포에있어서는 1군은대뇌부챗살에 1명, 속섬유막 2명, 뇌간 2명의분포를보였고, 2 군은대뇌부챗살에 2명, 속섬유막 2명, 뇌간 2명으로, 전반적으로고른분포를보였다. 연령은각군간에유의한차이를보이지는않았으나 (p= 0.802), 성별은 2군에서는남자가 4군에서는여자가더많은비율을보였다 (Table 1). 이는각군간환자수가비슷하지않아나타난결과로추정된다. 뇌자기공명영상촬영은 1군이증상발생 36.4 시간, 2군은 33.8 시간, 3군은 31.2 시간, 4군은 34.7 시간이지나서검사하여각군간에통계학적인차이를보이지는않았다 (p>0.05). 활성 MMP-9 측정을위한혈액채취는 1군이증상발생 28 시간, 2군 은 26.1 시간, 3군은 25.4 시간, 4군은 27.9 시간이지난시점에서채취되었다. 뇌혈관위험인자는고혈압, 당뇨, 심장질환, 고지혈증, 흡연모두각군간에통계학적으로유의있는차이를보이지는않았다 (p>0.05)(table 1). 내원당시시행한체온과수축기, 이완기혈압도또한각군간에차이가없었다 (Table 2). 그러나검사실척도로시행한 ESR 이 1군이 17±2.7, 2군이 23.5±4.6 여서, 3군의 14.83±2.1, 4군의 13.65±1.8 보다통계학적으로유의하게높게측정되었다 (p=0.028). 또한다른염증에대한표식인자인 CRP 도통계학적으로유의하지는않았지만, 1군과 2군이 3군이나 4군보다 CRP 수치가높은경향을보였다 (p=0.062). 그러나그이외의검사실척도인 RBC, Hct, WBC, Table 2. Comparisons of laboratory parameters in each group. Among the parameters, only ESR level was significantly elevated in group 1, 2 (p<0.05) Group 1 (n=5) Group 2 (n=6) Group 3 (n=25) Group 4 (n=52) P-value a BT ( ) SBP (mmhg) DBP (mmhg) Hematocrits (%) Glucose (mg/dl) LDL (mg/dl) HDL (mg/dl) TG (mg/dl) Leukocyte (cells/mm 3 ) ESR (mm/hr) CRP (mg/dl) aptt (sec) PT (%) Fibrinogen (mg/dl) AT III D-dimer NSE (ng/dl) 36.34±0.2 157.78±33.1 92.22±12.0 39.02±12.0 150.56±31.6 99.97±21.8 33.79±10.75 149.86±103.1 7044.44±856.8 17±2.7 0.83311±0.4 28.14±3.2 99.93±11.9 358.56±34.1 78.522±3.5 0.167±0.03 11.867±2.1 36.36±0.26 150.01±21.8 87.14±9.1 40.35±3.3 146.5±48.8 110.92±30.9 33.03±6.8 148.34±56.4 7821.43±1051.9 23.5±4.6 0.89836±0.3 27.04±2.5 98.78±13.2 392.86±28.9 81.7636±4.6 0.157±0.02 9.964±0.9 36.33±0.23 151.74±32.8 90.87±18.8 39.98±2.9 153.91±52.3 105.65±20.9 34.78±7.80 149.89±69.4 6960.87±418.8 14.83±2.1 0.48587±0.1 29.05±4.9 97.35±16.5 340.78±13.3 81.2778±3.5 0.148±0.01 13.461±1.2 36.31±0.24 148.05±20.9 92.25±9.8 40.26±3.9 157.35±74.2 112.37±34.4 34.02±6.67 150.02±80.6 7285.65±546.2 13.65±1.8 0.3343±0.1 28.09±4.2 96.94±14.0 354.45±17.0 82.483±3.3 0.14±0.01 10.64±1.1 0.822 0.885 0.284 0.391 0.762 0.888 0.895 0.89 0.712 0.028 0.062 0.123 0.78 0.34 0.94 0.592 0.079 ±SD, a by Kruskal Wallis test. 314 J Korean Neurol Assoc Volume 24 No. 4, 2006
지는않았다. 입원당시와 14일후시행한 NIHSS 점수로비교한신경학적악화정도는허혈성병변에미세출혈을보인경우 (1군, 2군 ) 가허혈성병변에미세출혈을보이지않은경우 (3군, 4군 ) 에비해신경학적으로악화된경우가많았다 (p<0.05). 그러나, 3군과 4 군간의신경학적악화정도는통계학적인차이를보이지않았다 (Fig. 3). Figure 2. Relationship between MMP-9 activity and patterns of microbleeds. MMP-9 activity was significantly increased in all groups having microbleeds(group 1, 2, 3) when compared with group showing no evidence of microbleeds in GRE (p<0.05, Duncan s multiple range test). a <0.05, b <0.01 (when compared with group 4), c <0.05 (when compared with group 3). 고찰 경사에코자기공명영상에서저음영병소를보이는미세출혈은뇌혈관기저막의파괴와연관된다고알려져있다. 세포외기질 (extracellular matrix) 은세포와조직의구조를유지하는데중요한역할을한다. 7 뇌혈관기저막 (basement membrane; basal lamina) 은 type IV collagen, laminin, fibronectin 등 의세포외기질로구성되어있으며혈액뇌장벽 (blood brain barrier) 의안정에큰역할을한다. 7 뇌경색시에는뇌혈관기저막이파괴되는데, 8 이는뇌경색시동반되는뇌부종과출혈전환의일차적인원인으로생각되고있다. 7,9,10 기저막을파괴하는물질중가장대표적이고중요한것이 MMP이다. 7,11 MMP 중 MMP-9 는 gelatinase B로도불리며뇌의기저막을구성하는주요세포외기질인 type IV collagen 이나 laminin 등을주로파괴하기때문에여러중추신경계질환 Figure 3. Comparision between pattern of microbleeds (group 1, 2; microbleed in acute ischemic lesion, group 3, 4; silent microbleeds or absence of microbleeds) and neurologic progression of lacunar stroke (p<0.05, chi-square test). a <0.05. PLT 용적, 그리고혈당, 지질 (LDL, HDL, TG), fibrinogen, activated partial thromboplastin time, prothrombin time, AT III, D-dimer, NSE 등의수치는각군간에유의있는차이를보이지않았다 (p>0.05)(table 2). 표준정량적 ELISAs 로측정한 MMP-9 는 GRE 상미세출혈이발견되었던경우 (1군, 2군, 3군 ) 가미세출혈이발견되지않았던경우 (4군 ) 에비해증가되었으며 (p<0.05), 허혈성병변에만미세출혈을보였던경우 (1군 ) 나허혈성병변과함께다른곳에미세출혈을보였던경우 (2군 ) 는다른곳에만미세출혈을보인경우 (3군 ) 에비해활성 MMP-9 가통계학적으로유의하게증가되었다 (p<0.01)(fig. 2). 입원당시시행한 NIHSS 점수는 1군이 4.4 점, 2군이 4.2 점, 3군이 3.9 점, 4군이 3.4 점을보여각군간에유의차이를보이 에서중요한역할을할것으로생각되며다발성경화증과뇌종양등에서 MMP-9 이증가한다고보고되었다. 7,12,13 MMP 는뇌혈관기저막을파괴하는대표적인물질이기때문에 MMP 의증가와출혈전환이서로연관되어있을가능성이크다. 실제로 baboon 에서 MMP-9 의증가와뇌경색후의출혈전환이연관되어있다는것이밝혀졌고 7,14 최근에는토끼에서 MMP 억제제를 t-pa와동시에사용하면출혈전환을현저히줄일수있다고보고되었다. 7,15 Gasche 등은마우스뇌경색모델에서 MMP-9 의증가가뇌경색후의혈액뇌장벽의파괴와연관이있다고보고하였으며 7 저자들의최근연구에의하면동물뇌경색모델에서염증반응유도및활성은 MMP-9 의증가와연관이있다는사실을보고한바있다. 16,17 그러나염증반응과 MMP-9 의증가와의관련성에대한저자들의이전의연구가활성 MMP-9 를 ELISA 로측정한것이아니라, zymography 로 2번측정하여상대적인증가또는감소를비율로측정한것이기때문에한계점이있었다. 열공성뇌경색에서도이런혈액뇌장벽의파괴와연관되어뇌경색부위에미세출혈이발생할수있다. 일반적인뇌전산화단층촬영에서도보이지않고, GRE 에서둥근모양의저음영으로 J Korean Neurol Assoc Volume 24 No. 4, 2006 315
관찰된다. Schonewille 등은열공성경색의약반수에서이런미세출혈이존재하며, 기저의소혈관질환을반영한다고주장하였으나, 그의연구는미세출혈과허혈성병변과의연관을보지는않았다. 18 이번연구에서열공성뇌경색때 GRE 상허혈성부위에미세출혈이발생한경우는전체의 12.5% 를차지하였고, 허혈성병변뿐만아니라다른곳에서도 GRE 에서미세출혈이발견된경우는전체의 36.7% 를보였다. 미세출혈은기저의고혈압등의뇌혈관성질환의위험인자나나이와도연관될수있다고하였으나 2 이번연구에서는각군간에뇌혈관성질환의위험인자나나이는통계학적인차이를보이지않아큰문제는없을것으로생각된다. MMP-9 의활성도에영향을미치는인자에대해서는여러보고가있는데 Paolo 등은 iron 등의혈액분해산물이 MMP-9 의활성도증가와연관이있다고주장한바있다. 19 그러므로, 미세출혈이 ferritin, iron, hemosiderin 등의침착에의해생기는것이기때문에이번연구결과와같이열공성경색때내원당시 GRE 에서미세출혈을보인경우활성 MMP-9 의증가와연관되었다고생각한다. 또한허혈성병변이외의부분에만미세출혈이있었던곳에서도미세출혈이없었던경우에비해활성 MMP-9 가더증가되어있었는데아마도기저의고혈압등의원인에의해미세출혈이존재하던상태에서뇌경색이발생하여활성 MMP-9 가더증가된것으로생각한다. 뇌경색후 MMP-9 의활성도의증가시점은연구자마다다르게보고하고있으나, 동물실험에서뇌경색이있은후 2시간이후부터증가되기시작하여 6일이지나서도계속증가되었다는결과가있다. 7 이번연구에서는뇌경색이발생한지 48시간이내의열공성경색환자를대상으로하여활성 MMP-9 를 1회만측정하였으므로, 추후시간경과에따라활성 MMP-9 를여러차례측정해야할것으로생각한다. 열공성경색의초기신경학적악화에여러인자들이관여할수있다. 당뇨, 입원당시의근력정도, 20 측부순환의혈역학적장애정도, 21 glutamate 와 GABA 의불균형, 22 inflammatory cytokine, 23 그리고체온, 백혈구와 fibrinogen 수치등의급성기인자들이열공성경색의예후와관련될수있다는보고들이있었다. 19 그러나정확한기전은아직밝혀진것이없다. 본저자들은이전의연구에서열공성경색의초기신경학적악화에국소적인염증반응이중요하며, 여러염증인자중활성 MMP-9 가특히연관성이높다고보고한바있다. 6 또한이번연구결과를보면열공성경색시허혈성병변에미세출혈을보인경우가초기신경학적악화와연관되어있었는데, 이런결과는아마도국소적인염증성반응과활성 MMP-9 의증가와연관되었을것으로생각된다. 그러므로열공성경색의초기신경학적악화에대한예측인자로서내원당시의 MMP-9 의활성도뿐만아니라 GRE 상보이는미세출혈의유무도의미를가질수있을것으로생각한다. 그러나본연구에서는 microbleeds 개수와 MMP-9 활성도와의정량적분석은각군별대상환자의수가충분치못하여정확히분석하지못한것이제한점으로나타나며, 다수의대상을통한추후연구가필요할것이다. REFERENCES 1. Jeerakathi T, Wolf P, Beiser A, John K, Au R, Kase CS, et al. Cerebral microbleeds: prevalence and associations with cardiovascular risk factors in the Framingham study. Stroke 2004;35: 1831-1835. 2. Kinoshita T, Okudera T, Tamura H, Ogawa T, Hatazawa J. Assessment of lacunar hemorrhage associated with hypertensive stroke by echo-planar gradient-echo T2*-weighted MRI. Stroke 2000;31:1646-1650. 3. Kidwell C, Saver J, Villablance P, Duckwiler G, Fredieu A, Gough K, et al. Magnetic Resonance Imaging detection of microbleeds before thrombolysis: An Emerging Application. Stroke 2002; 33:95-98. 4. Fazekas F, Kleinert R, Roob G, Kleinert G, Kapeller P, Schmidt R, et al. Histopathologic analysis of foci of signal loss on gradientecho T2*-weighted MR images in patients with spontaneous intracerebral hemorrhage : evidence of microangiopathy-related microbleeds. Am J Neuroradiol 1999;20:637-642. 5. Audebert HJ, Pellkofer TS, Wimmer ML, Haberl RL. Progression in lacunar stroke is related to elevated acute phase parameters. Eur Nruol 2004;51:125-131. 6. Kim YS, Lee KY, Koh SH, Park CY, Kim HY, Lee YJ, et al. The Role of matrix metalloproteinase-9 in the early neurological worsening of acute lacunar infarctions. Eur Neurol 2006;55:11-15. 7. Lee KY, Yang WS, Kim EH, Heo JH, Kim DG. The temporal changes of matrix metalloproteinase in experimental middle cerebral artery occlusion and reperfusion. J Korean Neurol Assoc 2001;19: 278-284. 8. Hamann GF, Okada Y, Fitridge R, del Zoppo GJ. Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke 1995;26:2120-2126. 9. Hamann GF, Okada Y, del Zoppo GJ. Hemorrhagic transformation and microvascular integrity during focal cerebral ischemia/ reperfusion. J Cereb Blood Flow Metab 1996;16:1373-1378. 10. Okada Y, Copeland BR, Fitridge R, Koziol JA, del Zoppo GJ. Fibrin contributes to microvascular obstructions and parenchymal changes during early focal ischemia and reperfusion. Stroke 1994; 25:1847-1853. 11. Venti M, Parnetti L, Silvestrelli G, Gallai V. Role of neuroprotective drugs in acute ischemic stroke. Cerebrovasc Dis 2000;10:24-26. 12. Anthony DC, Ferguson B, Matyzak MK, Miller KM, Esiri MM, Perry VH. Differential matrix metalloproteinase expression in cases of multiple sclerosis and stroke. Neuropathol Appl Neurobiol 1997; 316 J Korean Neurol Assoc Volume 24 No. 4, 2006
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